Impact of myeloperoxidase and NADPH-oxidase polymorphisms in drug-induced agranulocytosis

被引:49
作者
Mosyagin, I
Dettling, M
Roots, I
Mueller-Oerlinghausen, B
Cascorbi, I
机构
[1] Ernst Moritz Arndt Univ Greifswald, Inst Pharmacol, Greifswald, Germany
[2] Dept Psychiat, Franklin, Germany
[3] Inst Clin Pharmacol, Berlin, Germany
[4] German Med Assoc, Berlin, Germany
关键词
D O I
10.1097/01.jcp.0000144891.52858.a6
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Therapy of the atypical antipsychotic drug clozapine is limited by a comparatively high incidence of agranulocytosis in 0.8% of patients. This severe side effect is possibly based on the clozapine-mediated stimulation of cytokines and soluble cytokine receptors release, followed by induction of granulocyte proliferation and induction of myeloperoxidase (MPO) and NADPH-oxidase. Because NADPH-oxidase/MPO may oxidize clozapine to highly reactive nitrenium ions, we investigated the role of hereditary polymorphisms in the NADPH oxidase/myeloperoxidase system in agranulocytosis patients who received clozapine (n = 49), ticlopidine (n 11), and other drugs prior to the event. The low active MPO -436A allelic variant frequency was 22.2% in cases and 19.9% in controls, but AA carriers were overrepresented among cases compared with the sum of AG and GG-carriers (odds ratio 4.16, 95% confidence limits 0.86-20.3, P= 0.056). Particularly in clozapine-induced agranulocytosis, this finding was most pronounced (P = 0.04). In the CYBA gene, encoding the p22phox subunit of the NADPH-oxidase, 2 polymorphisms were investigated. C242T (His72Tyr) had an allele frequency of 31.9% and 32.2% (P = NS) and A640G in the 3'-UTR was less frequent in cases (48.7%) than controls (60.0%), odds ratio 0.63 (0.39-1.02), P = 0.048. CYBA 640GG-carriers were marginally less frequent in cases compared with controls (28.2% vs. 38.7%, P = 0.062). Sequencing the entire coding region of the NADPH subunit CYBB (gpSlphase) disclosed that CYBB is a highly conserved gene, which does not represent a risk factor for clozapine-induced agranulocytosis. The impact of the polymorphic myeloperoxidase, however, needs further verification to predict a patient's risk to develop drug-induced agrarnuloctosis.
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页码:613 / 617
页数:5
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